Identification of short functional motifs as potential drug targets for HIV

鉴定短功能基序作为 HIV 潜在药物靶标

• 批准号: 7915001
• 负责人: MARTIN R SCHILLER
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915001
• 关键词: Active Sites; Affect; Amino Acid Motifs; Autoimmune Process; Binding; Binding Sites; Biological Assay; CD4 Lymphocyte Count; Cells; Classification; Collaborations; Collection; Consensus; Consensus Sequence; DNA; Databases; Dimerization; Drug Delivery Systems; Enzymes; Epidemic; Finland; Goals; HIV; HIV Infections; HIV Integrase; HIV Protease; ITIM; Internet; Intervention; Lead; Letters; Libraries; Life Cycle Stages; Lipids; Literature; Maps; Membrane Proteins; Mutagenesis; Mutate; Mutation; NMR Spectroscopy; Nucleic Acids; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Post-Translational Protein Processing; Process; Protein Binding; Proteins; RNA-Directed DNA Polymerase; Research Infrastructure; Research Personnel; Resistance; Retroviridae; Screening procedure; Structure; Surface; Symptoms; Syndrome; System; Testing; Treatment Protocols; Universities; Viral; Viral Genome; Virus; Virus Diseases; arginylarginine; clinically significant; env Gene Products; follow-up; new therapeutic target; platform-independent; protein structure; recombinant virus; research study; small molecule; src Homology Region 2 Domain; three dimensional structure; tool; trafficking; web site

Autoimmune Deficiency Syndrome (AIDS) is caused by the HIV retrovirus and is a deadly worldwide epidemic. One efficient strategy that viruses use is to hijack short functional motifs. These motifs are consensus sequences on different HIV proteins that are the binding sites or targets that host proteins act on to allow viral infection and replication. For example, the HIV envelope polyprotein (Env) contains a short consensus motif (Arg-x-Lys/Arg-Arg; x is any residue) for cleavage by the host protease, Furin. One of the major limitations in identifying short functional motifs is the lack of a systematic approach and simple accessibility for HIV researchers. Our cross-disciplinary team has built Minimotif Miner (MnM), a motif database and platform-independent web-tool that identifies short motif consensus sequences (less than 15 residues) in protein queries and thus new potential functions in these proteins (http://mnm.engr.uconn.edu/). Many of these consensus sequences are present in HIV proteins. To facilitate the study of short functional motifs in HIV proteins, we proposed to provide a free new web system infrastructure that integrates information for protein motifs with sequence conservation among HIV isolates and 3D structures of HIV proteins to allow HIV researchers to explore new functions in HIV proteins. Short functional motifs provide a plethora of potential targets for intervention in the viral life-cycle that have not been thoroughly explored (R21, Aims 1 and 2). A second goal of this proposal is to test some of the more exciting motif predictions. Consensus motifs in HIV proteins will be validated by mutating the motif in recombinant viruses, testing for the effect of the mutation on viral infection and replication, and then assaying the direct function of the predicted motif (e.g. interaction with another protein; aims 3 and 4.). Validated motifs we be further examined in the R33 component by screening a compound library by Nuclear Magnetic Resonance spectroscopy to identify lead compounds, which will then be tested for inhibition of viral infection and replication (Aims 5 and 6).This project provides a key tool to help understand the process by which HIV infects and replicates within cells. The proposed experiments are likely to identify new lead compounds for treating HIV infection.

自身免疫缺陷综合症（艾滋病）是由 HIV 逆转录病毒引起的， 一种致命的全球流行病。病毒使用的一种有效策略是劫持 简短的功能性图案。这些基序是不同 HIV 的共有序列 蛋白质是宿主蛋白质作用的结合位点或目标，以允许病毒 感染和复制。例如，HIV 包膜多蛋白 (Env) 包含一个短的共有基序（Arg-x-Lys/Arg-Arg；x 是任何残基） 被宿主蛋白酶弗林蛋白酶切割。识别的主要限制之一 短功能主题缺乏系统的方法和简单的 艾滋病毒研究人员的可及性。我们的跨学科团队打造了 Minimotif Miner (MnM)，一个主题数据库和独立于平台的网络工具，用于识别 蛋白质查询中的短基序共有序列（少于 15 个残基）和 因此这些蛋白质具有新的潜在功能（http://mnm.engr.uconn.edu/）。 许多共有序列存在于 HIV 蛋白中。为了方便 研究 HIV 蛋白中的短功能基序，我们建议提供免费的 新的网络系统基础设施将蛋白质基序信息与 HIV 分离株之间的序列保守性和 HIV 蛋白的 3D 结构 允许艾滋病毒研究人员探索艾滋病毒蛋白质的新功能。短功能性 基序为干预病毒生命周期提供了大量潜在目标 尚未被彻底探索（R21，目标 1 和 2）。第二个目标是 这个提议是为了测试一些更令人兴奋的主题预测。共识 HIV 蛋白中的基序将通过突变重组体中的基序来验证 病毒，测试突变对病毒感染和复制的影响，以及 然后分析预测基序的直接功能（例如与 另一种蛋白质；目标 3 和 4。）我们将在中进一步检查经过验证的主题 通过核磁筛选化合物库来筛选R33组分 共振光谱法识别先导化合物，然后进行测试 抑制病毒感染和复制（目标 5 和 6）。该项目提供了一个关键工具，帮助了解 HIV 感染和复制的过程 在细胞内复制。 拟议的实验可能会发现新的先导物质 用于治疗HIV感染的化合物。

项目成果

The Geogenomic Mutational Atlas of Pathogens (GoMAP) web system.

病原体地理基因组突变图谱 (GoMAP) 网络系统。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Sargeant, David P;Hedden, Michael W;Deverasetty, Sandeep;Strong, Christy L;Alaniz, Izua J;Bartlett, Alexandria N;Brandon, Nicholas R;Brooks, Steven B;Brown, Frederick A;Bufi, Flaviona;Chakarova, Monika;David, Roxanne P;Dobritch, Karlyn M;Guer
• 通讯作者: Guer